Inflammatory diseases of the bowel is the general term for diseases that cause inflammation of the intestines such as irritable bowel syndrome (IBS), and the inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease that are chronic inflammatory disorders of the gastrointestinal (GI) tract. For example, ulcerative colitis is an IBD that causes inflammation of the mucosa lining of the large intestine, usually occurring in the rectum and lower part of the colon, but it may affect the entire colon. Crohn's disease may affect any section of the GI tract (i.e. mouth, oesophagus, stomach, small intestine, large intestine, rectum and anus), and may involve all layers of the intestinal wall. The cause of many of these diseases is unknown.
IBS is a functional gastrointestinal disorder in which abdominal discomfort or pain is associated with defecation or change in bowel habit, and with features of disordered defecation. Theses symptoms represent a condition in which disturbances in motor and/or sensory function of the gut may be associated with psychosocial disorders, and the interaction leads to symptoms at several levels of the gastrointestinal tract.
IBS is now considered to be the most common gastrointestinal disorder. Prevalence in western world is estimated to be 15-20% of the adolescent and adult population and the disorder accounts for 20-50% of the referrals to gastroenterology clinics.
Current approaches to management of IBS consist of identification of symptoms consistent with the syndrome and the exclusion of organic disease with similar presentation, followed by non-pharmacological and pharmacological therapies, where appropriate. Current pharmacological therapeutic options are limited and the effectiveness of many is poorly documented. The current pharmacological therapies aim at treating symptoms with the rationale being either to modulate intestinal motility, decrease visceral sensitivity or treat associated disorders, particularly anxiety or depression.
The most common symptoms of IBD include abdominal pain, tenesmus, fecal urgency and bloody diarrhoea. Sufferers may also experience fatigue, weight loss, loss of appetite, rectal bleeding and loss of body fluids and electrolytes. The symptoms of the disease are usually progressive, and sufferers typically experience periods of remission followed by severe flare-ups.
Despite the prevalence of IBD (it affects an estimated 2 million people in the United States alone), there is no cure and the exact causes of the disease are not yet understood. Conventional treatments for IBD have involved anti-inflammatory drugs, immunosuppressive drugs and surgery. However, many of the drugs used for treating the disease have negative side effects such as nausea, dizziness, anaemia, leukopaenia, skin rashes and drug dependence, and the surgical procedures are often radical procedures, such as intestinal resectomy and colectomy.
This has led to several investigators to attempt to identify new and novel drugs for treatment of the inflammatory diseases of the bowel. Unfortunately, the very nature of the disease means that screening and measuring the efficacy of potential treatments in human subjects is very difficult. Often, the results of human trials depend upon subjective testimony from the trial candidates themselves, with little or no biochemical or physiological data to substantiate claims. Animal models may be used to allow tissue sections from affected organs to be taken, but drugs effective in animal models do not always have the same efficacy in humans.
The control of inflammatory diseases is exerted at a number of levels. The controlling factors include hormones, prostaglandins, reactive oxygen and nitrogen intermediates, leukotrienes and cytokines. Cytokines are low molecular weight biologically active proteins that are involved in the generation and control of immunological and inflammatory responses. A number of cell types produce these cytokines, with neutrophils, monocytes and lymphocytes being the major sources during inflammatory reactions due to their large numbers at the injured site.
Multiple mechanisms exist by which cytokines generated at inflammatory sites influence the inflammatory response. Chemotaxis stimulates homing of inflammatory cells to the injured site, whilst certain cytokines promote infiltration of cells into tissue. Cytokines released within the injured tissue result in activation of the inflammatory infiltrate. Most cytokines are pleiotropic and express multiple biologically overlapping activities. Cytokine cascades and networks control the inflammatory response, rather than the action of a particular cytokine on a particular cell type. As uncontrolled inflammatory responses can result in diseases such as inflammatory diseases of the bowel, it is reasonable to expect that cytokine production has gone astray in individuals affected with these diseases. However, as many cytokines may have both pro- and anti-inflammatory activities, it is very difficult to attribute disease symptoms, or recovery there from, with a particular individual cytokine.
Based on the forgoing, it is desirable to provide methods for screening and measuring the efficacy of potential treatments for inflammatory diseases of the bowel in humans or other mammals that generate biochemical or physiological data. This data could be used to evaluate the efficacy of the treatment. It is further desirable to provide methods for measuring changes in the levels of specific cytokines potentially involved in the pathogenesis of inflammatory diseases of the bowel such that the prognosis and disease progression of a subject with inflammatory diseases of the bowel can be monitored.